JPH0892096A - Inhibitors of vascular smooth muscle cell proliferation or migration - Google Patents

Abstract

(57) [Summary] [Purpose] Activity to inhibit proliferation and migration of vascular smooth muscle cells
To obtain a drug having Especially for prevention of restenosis after PTCA
Or get a therapeutic agent. [Constitution] The following formula (1) (In the formula, W is a phenylene group, C₃~ C₇Cycloalkyle
R group, thiophenediyl group, R¹Is a hydrogen atom,
Methyl group, ethyl group, vinyl group, R²Is C₃~ C₉A
Alkyl group, alkenyl group, alkynyl group, C₃~ C₇Shi
Represents a chloroalkyl group. R³⁰Is a hydrogen atom, C₁~ C_Ten
Alkyl group, phenyl group, benzyl group, naphthyl group,
Or 1 equivalent of cation, Z^Ten, Z²⁰Is hydrogen
Child, bird (C ₁~ C₇(Hydrocarbon) silyl group, or oxygen
Form acetal or ester bond with atom
Represents a group. m represents 0 or 1 and n represents 0 to 4
You ) Isocarbacyclines and / or
Or vascular smooth muscle cells containing its enantiomer as an active ingredient.
Vesicle growth or migration inhibitors.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an inhibitor of proliferation or migration of vascular smooth muscle cells containing isocarbacyclins and / or enantiomers thereof as an active ingredient.

[0002]

2. Description of the Related Art Prostaglandins have various physiological actions such as strong platelet aggregation inhibitory action, vasodilatory hypotensive action, gastric acid secretion inhibitory action, smooth muscle contraction action, cell protection action and diuretic action. , A compound useful for treating or preventing myocardial infarction, angina, arteriosclerosis, hypertension, duodenal ulcer, induction of labor, abortion and the like.

Natural prostacyclin is a local hormone produced mainly in the vascular endothelium in the living body, and has a strong physiological activity such as an inhibitory effect on platelet aggregation.
Attempts have been made to directly use this product as a drug by utilizing its vasodilatory action (PJLewis, JOGrad.
y, Clinical Pharmacology of Prostaglangin). However, since natural prostacyclin has an enol ether bond which is easily hydrolyzed in the molecule, it is easily deactivated under neutral or acidic conditions. Therefore, it cannot be said to be a preferable compound as a drug because of its chemical instability. Therefore, synthetic studies of chemically stable synthetic prostacyclin derivatives that show the same activity as natural prostacyclin have been earnestly conducted (Synthsis, 198).
4,449). Of these, 0 (O) -methano-Δ ^{6 (9),} which is a prostacyclin that fully satisfies the chemical stability, by replacing the 6th and 9th oxygen atoms of prostacyclin with a methine group (-CH = ^). Synthesized α-prostaglandins I ₁ (isocarbacyclines), which show potent biological activity such as inhibitory effect on platelet aggregation and vasodilatory hypotensive activity comparable to natural prostacyclin, and are considered to be useful as pharmaceuticals. (Japanese Patent Laid-Open No. 59-210
044, JP-A-61-197518).

On the other hand, percutaneous coronary angioplasty (hereinafter referred to as "PT
CA) is a treatment method for ischemic heart disease, which is a method that has progressed rapidly in recent years because it has a low degree of invasiveness to patients and an excellent initial treatment effect, and there are over 30,000 cases annually in Japan. It is said that there are 300,000 surgical operations in the United States. However, the biggest drawback of coronary restenosis appearing within a few months after surgery in 30-40% of patients after PTCA remains unsolved. As a mechanism of restenosis generation after PTCA, “vascular disorder-reaction hypothesis” by R. Ross, that is, vascular endothelial cell disorder caused by some cause causes adhesion and aggregation of platelets to the lesion site, and PDGF and It has been widely accepted that the hypothesis that arteriosclerosis is established by the secondary proliferation of vascular smooth muscle cells and intercellular substances under the intimal membrane due to the release of cytokines. Therefore, clinical trials for preventing restenosis after PTCA with antiplatelet agents, anticoagulants, etc. have been attempted, but at present, no drug having a clinically sufficient effect has been found. In addition, compounds that suppress one or both of "migration of vascular smooth muscle cells from the intima to the media and proliferation in the media", which are deeply involved in the mechanism of restenosis, also prevent the restenosis. Although strongly expected as a drug, a clinically effective drug has not been found yet.

The isocarbacyclines having a phenylene group or the like in the α chain represented by the above (1) used in the present invention are novel compounds and have no physiological activity such as vascular smooth muscle cell proliferation or migration inhibitory action. unknown.

[0006]

The problem to be solved by the present invention is to find a drug having an inhibitory effect on proliferation or migration of vascular smooth muscle cells, which is expected as a drug for preventing restenosis after PTCA. Is.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies based on the above object, and as a result, the isocarbacyclines represented by the above formula (1) have an inhibitory effect on the proliferation or migration of vascular smooth muscle cells. As a result of further finding out that they have the above and continuing the research, they have reached the present invention.

That is, the present invention provides the following formula (1)

[0009]

[Chemical 2]

(Wherein W represents an ortho, meta or para phenylene group, a C ₃ -C ₇ cycloalkylene group or a thiophenediyl group, and R ¹ represents a hydrogen atom, a methyl group, an ethyl group or vinyl. Represents a group, and R ² represents a linear or branched C ₃ -C ₉ alkyl group, an alkenyl group, or an alkynyl group, which may be substituted, or a C ₃ -C ₇ cycloalkyl group. ³⁰
Represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a phenyl group, a benzyl group, a naphthyl group, or 1 equivalent of a cation, and Z ¹⁰ and Z ²⁰ are the same or different and each represents a hydrogen atom, a tri (C ₁ -C ₇ (Hydrocarbon) silyl group, or a group that forms an acetal bond or an ester bond together with the oxygen atom to which it is bonded. n is 0 or 1, and m is an integer of 0-4. ) Is an inhibitor of the proliferation or migration of vascular smooth muscle cells containing the isocarbacyclins and / or the enantiomer thereof as an active ingredient.

In the above formula (1), W is ortho, meta,
It represents a para phenylene group, a C ₃ -C ₇ cycloalkylene group, or a thiophenediyl group, and W is preferably an ortho, meta, or para phenylene group.

In the above formula (1), Z ¹⁰ and Z ²⁰ are
The same or different, and represents a hydrogen atom, a tri (C ₁ -C ₇ hydrocarbon) silyl group, or a group forming an acetal bond or an ester bond with the oxygen atom to which it is bonded.

Z^Ten, Z²⁰The bird (C₁~ C₇hydrocarbon)
Examples of the silyl group include a trimethylsilyl group and a triethyl group.
Cylsilyl group, triisopropylsilyl group, t-butyl
Tri (C such as dimethylsilyl group₁~ C_FourAlkyl)
Silyl group; dif such as t-butyldiphenylsilyl group
Phenyl (C₁~ C_FourAlkyl) silyl group; dimethylphen
Di (C₁~ C_FourAlkyl) pheny
Rusilyl group and tribenzylsilyl group are also preferred.
Can be listed as Bird (C₁~ C _FourArchi
) Silyl group, diphenyl (C₁~ C_FourAlkyl) siri
Group is preferred, and t-butyldimethylsilyl group is particularly preferred.
Particularly preferred.

The group forming an acetal bond with the oxygen atom to which it is bonded is, for example, a methoxymethyl group, a 1-ethoxyethyl group or a 2-methoxy-2 group.
-Propyl group, 2-ethoxy-2-propyl group, (2-
Mention may be made of a methoxyethoxy) methyl group, a benzyloxymethyl group, a 2-tetrahydropyranyl group or a 2-tetrahydrofuranyl group. A 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, a 1-ethoxyethyl group, a 2-ethoxy-2-propyl group and a (2-methoxyethoxy) methyl group are preferable, and a 2-tetrahydropyranyl group is particularly preferable.

The group forming an ester bond with the oxygen atom to which it is bonded is, for example, a C ₁ -C ₅ acyl group such as formyl group, acetyl group, propionyl group, butanoyl group, pentanoyl group, benzoyl group or toluyl. A group etc. can be mentioned. An acetyl group and a benzoyl group are particularly preferable. Of these, hydrogen atoms are preferable as both Z ¹⁰ and Z ²⁰ .

In the above formula (1), R ¹ represents a hydrogen atom, a methyl group or a vinyl group. As R ¹ , n =
When 0, a hydrogen atom is preferable, and when n = 1, a methyl group is preferable.

In the above formula (1), R ² is a linear or branched C ₃ -C ₉ alkyl group which may be substituted,
It is an alkenyl group, an alkynyl group, or represents a C ₃ -C ₇ cycloalkyl group.

A straight chain or branched chain unsubstituted C _{3 of} R ²
To C ₉ alkyl groups include, for example, n-propyl group, i
so-propyl group, n-butyl group, sec-butyl group,
tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-decyl group,
1-methylpentyl group, 1-methylhexyl group, 1,1
-Dimethylpentyl group, 2-methylpentyl group, 2-methylhexyl group, 5-methylhexyl group, 2,5-dimethylhexyl group and the like. Of these, n-
Butyl group, n-pentyl group, n-hexyl group, (R)-
Alternatively, (S)-or (RS) -1-methylpentyl group, (R)-or (S)-or (RS) -2
-Methylhexyl group and the like are preferable. Also, the substituted C
_{As the 3 to} C ₉ alkyl group and the C _{3 to} C ₉ alkyl group moiety, the same ones can be preferably used. And, examples of the substituent moieties C ₃ -C ₆ cycloalkyl group is preferred.

The linear or branched C ₃ -C ₉ alkenyl group for R ² is, for example, 2-butenyl group, 2-pentenyl group, 3-pentenyl group, 2-hexenyl group, 4-
Examples thereof include a hexenyl group, a 2-methyl-4-hexenyl group, a 6-methyl-5-heptenyl group and the like.

The linear or branched C ₃ -C ₉ alkynyl group for R ² is, for example, 2-butynyl group, 2-pentynyl group, 3-pentynyl group, 2-hexynyl group, 4-
Hexynyl group, 2-octynyl group, 1-methyl-3-pentynyl group, 1-methyl-3-hexynyl group, 2-methyl-4-hexynyl group and the like can be mentioned.

Examples of the C ₃ -C ₇ cycloalkyl group for R ² include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and a cyclodecyl group. Of these, cyclopentyl group, cyclohexyl group and the like are preferable.

R³⁰Is a hydrogen atom, C₁~ C_TenThere is a linear
Or branched alkyl group, phenyl group, benzyl group,
Represents a futyl group, or 1 equivalent of cation. C₁~ C
_TenAs the alkyl group of, for example, a methyl group, an ethyl group,
n-propyl group, iso-propyl group, n-butyl group,
sec-butyl group, tert-butyl group, n-pentyl group
Group, n-hexyl group, n-heptyl group, n-octyl group
Group, n-nonyl group, n-decyl group, etc.
Can be. Above all, C₁~ C₆An alkyl group of, especially C₁
~ C_FourAlkyl groups of are preferred. 1 equivalent of cation
For example, Na ⁺, K⁺Alkali metal cations such as
1 / 2Ca²⁺, 1 / 2Mg²⁺, 1/3 Al³⁺Such as
Divalent or trivalent metal cations; ammonium io
Ammonium such as tetramethylammonium ion
Cations and the like. R³Especially as hydrogen
And a methyl group are preferable, and a methyl group is particularly preferable.

The 8-, 9-, 11-, 12- and 15-positions (n =) of the isocarbacyclines represented by the above formula (1)
The configuration of 0) is the same as that of natural prostacyclin. Here, the numbers are represented by the numbers at the corresponding positions of natural prostacyclin. Those having this configuration are particularly useful isomers, but the isocarbacyclines related to the present invention are those having such configuration, or their enantiomers, or all isomers derived from their asymmetric carbons. It includes the body.

The preferred specific examples of the isocarbacyclines used in the present invention are as follows, as a representative example of a compound in which Z ¹⁰ , Z ²⁰ and R ³⁰ are all hydrogen atoms. (01) (1 S , 5 S , 6 S , 7 R ) -3- (o-carboxybenzyl) -6-[(1 E , 3 S ) -3-hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-Octene, (02) (1 S , 5
S , 6 S , 7 R ) -3- (m-carboxybenzyl)-
6-[(1 E , 3 S ) -3-hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (03) (1 S , 5 S , 6 S , 7 R ) -3-
(P-Carboxybenzyl) -6-[(1 E , 3 S )-
3-hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (04) (1
S, 5 S, 6 S, 7 R) -3- (o- carboxybenzyl) -6 - [(1 E, 3 S) -3- hydroxy-4-methyl-1-octenyl] -7-hydroxy bicyclo [ 3.3.0] -2-Octene, (05) (1 S , 5
S, 6 S, 7 R) -3- (o- carboxybenzyl) -
6-[(1 E , 3 S ) -3-hydroxy-4,4-dimethyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (06) (1 S , 5
S, 6 S, 7 R) -3- (o- carboxybenzyl) -
6-[(1 E , 3 S ) -3-hydroxy-5-methyl-
1-octenyl] -7-hydroxybicyclo [3.3.
0] -2-octene, (07) (1 S , 5 S , 6 S ,
7 R ) -3- (o-carboxybenzyl) -6-[(1
E , 3 S ) -3-Hydroxy-5-methyl-1-nonenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (08) (1 S , 5 S , 6 S , 7 R ) -3-
(O-Carboxybenzyl) -6-[(1 E , 3 S )-
3-Hydroxy-3-cyclopentyl-1-propenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (09) (1 S , 5 S , 6 S , 7 R ) -3-
(O-Carboxybenzyl) -6-[(1 E , 3 S )-
3-hydroxy-3-cyclohexyl] -7-hydroxybicyclo [3.3.0] -2-octene, (10)
(1 S , 5 S , 6 S , 7 R ) -3- (o-carboxybenzyl) -6-[(1 E , 4 S ) -4-hydroxy-4
-Methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (11) (1 S , 5
S, 6 S, 7 R) -3- (o- carboxybenzyl) -
6-[(1 E , 4 R ) -4-hydroxy-4-methyl-
1-octenyl] -7-hydroxybicyclo [3.3.
0] -2-Octene, (12) (1 S , 5 S , 6 S ,
7 R ) -3- (o-carboxybenzyl) -6-[(1
E ) -4-Hydroxy-4-vinyl-1-octenyl]
-7-Hydroxybicyclo [3.3.0] -2-octene, (13) to (21) 3- (m-carboxybenzyl) derivative of each of (04) to (12), (22) to
(30) 3- (p-carboxybenzyl) derivative of each of (04) to (12),

(31) (1 S , 5 S , 6 S , 7 R )-
3- [2- (o-carboxyphenyl) ethyl] -6-
[(1 E , 3 S ) -3-Hydroxy-1-octenyl]
7-hydroxy-bicyclo [3.3.0] -2-octene, (32) (1 S, 5 S, 6 S, 7 R) -3- [2
-(O-Carboxyphenyl) ethyl] -6-[(1
E , 3 S ) -3-Hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-
Octene, (33) (1 S , 5 S , 6 S , 7 R ) -3
-[2- (o-carboxyphenyl) ethyl] -6-
[(1 E , 3 S ) -3-hydroxy-4,4-dimethyl-1-octenyl] -7-hydroxybicyclo [3.
3.0] -2-Octene, (34) (1 S , 5 S , 6
S , 7 R ) -3- [2- (o-Carboxyphenyl) ethyl] -6-[(1 E , 3 S ) -3-hydroxy-5-
Methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (35) (1 S , 5
S , 6 S , 7 R ) -3- [2- (o-carboxyphenyl) ethyl] -6-[(1 E , 3 S ) -3-hydroxy-5-methyl-1-nonenyl] -7-hydroxy Bicyclo [3.3.0] -2-octene, (36) (1 S ,
5 S , 6 S , 7 R ) -3- [2- (o-carboxyphenyl) ethyl] -6-[(1 E , 3 S ) -3-hydroxy-3-cyclopentyl-1-propenyl] -7- Hydroxybicyclo [3.3.0] -2-octene, (3
7) (1 S , 5 S , 6 S , 7 R ) -3- [2-(o-
Carboxyphenyl) ethyl] -6-[(1 E , 3 S )
-3-Hydroxy-3-cyclohexyl] -7-hydroxybicyclo [3.3.0] -2-octene, (38)
(1 S , 5 S , 6 S , 7 R ) -3- [2- (o-carboxyphenyl) ethyl] -6-[(1 E , 4 S ) -4
-Hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (3
9) (1 S , 5 S , 6 S , 7 R ) -3- [2-(o-
Carboxyphenyl) ethyl] -6-[(1 E , 4 R ).
-4-Hydroxy-4-methyl-1-octenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene,
(40) (1 S , 5 S , 6 S , 7 R ) -3- [2-
(O-Carboxyphenyl) ethyl] -6-[(1 E )
-4-Hydroxy-4-vinyl-1-octenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene,
(41)-(50) (31)-(40) Each 3-
[2- (m-carboxyphenyl) ethyl] derivative,
(51) to (60) Each of (31) to (40) 3-
[2- (p-carboxyphenyl) ethyl] derivative,

(61) (1 S , 5 S , 6 S , 7 R )-
3- [3- (o-carboxyphenyl) propyl] -6
-[(1 E , 3 S ) -3-hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (62) (61) 3- [3- (o- (Carboxyphenyl) propyl] derivative, (63) (61)
Bruno 3- [3- (m-carboxyphenyl) propyl] derivative, (64) (1 S, 5 S, 6 S, 7 R) -3-
[3- (o-carboxyphenyl) propyl] -6-
[(1 E , 3 S ) -3-Hydroxy-4-methyl-1-
Octenyl] -7-hydroxybicyclo [3.3.0]
-2-Octene, (65) (1 S , 5 S , 6 S , 7
R ) -3- [3- (o-carboxyphenyl) propyl] -6-[(1 E , 3 S ) -3-hydroxy-4,4
-Dimethyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (66) (1 S ,
5 S , 6 S , 7 R ) -3- [3- (o-carboxyphenyl) propyl] -6-[(1 E , 3 S ) -3-hydroxy-5-methyl-1-octenyl] -7- Hydroxybicyclo [3.3.0] -2-octene, (67)
(1 S , 5 S , 6 S , 7 R ) -3- [3- (o-carboxyphenyl) propyl] -6-[(1 E , 3 S ) -3
-Hydroxy-5-methyl-1-nonenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (6
8) (1 S , 5 S , 6 S , 7 R ) -3- [3-(o-
Carboxyphenyl) propyl] -6-[(1 E , 3
S ) -3-Hydroxy-3-cyclopentyl-1-propenyl] -7-hydroxybicyclo [3.3.0] -2
-Octene, (69) (1 S , 5 S , 6 S , 7 R )-
3- [3- (o-carboxyphenyl) propyl] -6
-[(1 E , 3 S ) -3-hydroxy-3-cyclohexyl] -7-hydroxybicyclo [3.3.0] -2-
Octene, (70) (1 S , 5 S , 6 S , 7 R ) -3
-[3- (o-Carboxyphenyl) propyl] -6-
[(1 E , 4 S ) -4-hydroxy-4-methyl-1-
Octenyl] -7-hydroxybicyclo [3.3.0]
-2-Octene, (71) (1 S , 5 S , 6 S , 7
R ) -3- [3- (o-carboxyphenyl) propyl] -6-[(1 E , 4 R ) -4-hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3. 0] -2-Octene, (72) (1 S , 5
S, 6 S, 7 R) -3- [3- (o- carboxyphenyl) propyl] -6 - [(1 E) -4- hydroxy-4
-Vinyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (73) to (81)
3- (3- (m-carboxyphenyl) propyl] derivatives of (64) to (72), (82) to (90)
3- [3- (p-carboxyphenyl) propyl] derivative of each of (64) to (72),

(91) (1 S , 5 S , 6 S , 7 R )-
3- [4- (o-carboxyphenyl) butyl] -6-
[(1 E , 3 S ) -3-Hydroxy-1-octenyl]
7-hydroxy-bicyclo [3.3.0] -2-octene, (92) (1 S, 5 S, 6 S, 7 R) -3- [4
-(O-Carboxyphenyl) butyl] -6-[(1
E , 3 S ) -3-Hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-
Octene, (93) (1 S , 5 S , 6 S , 7 R ) -3
-[4- (o-Carboxyphenyl) butyl] -6-
[(1 E , 3 S ) -3-hydroxy-4,4-dimethyl-1-octenyl] -7-hydroxybicyclo [3.
3.0] -2-Octene, (94) (1 S , 5 S , 6
S , 7 R ) -3- [4- (o-carboxyphenyl) butyl] -6-[(1 E , 3 S ) -3-hydroxy-5-
Methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (95) (1 S , 5
S, 6 S, 7 R) -3- [4- (o- carboxyphenyl) butyl] -6 - [(1 E, 3 S) -3- hydroxy-5-methyl-1-nonenyl] -7-hydroxy Bicyclo [3.3.0] -2-octene, (96) (1 S ,
5 S , 6 S , 7 R ) -3- [4- (o-carboxyphenyl) butyl] -6-[(1 E , 3 S ) -3-hydroxy-3-cyclopentyl-1-propenyl] -7- Hydroxybicyclo [3.3.0] -2-octene, (9
7) (1 S , 5 S , 6 S , 7 R ) -3- [4-(o-
Carboxyphenyl) butyl] -6-[(1 E , 3 S )
-3-Hydroxy-3-cyclohexyl] -7-hydroxybicyclo [3.3.0] -2-octene, (98)
(1 S , 5 S , 6 S , 7 R ) -3- [4- (o-carboxyphenyl) butyl] -6-[(1 E , 4 S ) -4
-Hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (9
9) (1 S , 5 S , 6 S , 7 R ) -3- [4-(o-
Carboxyphenyl) butyl] -6-[(1 E , 4 R ).
-4-Hydroxy-4-methyl-1-octenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene,
(100) (1 S , 5 S , 6 S , 7 R ) -3- [4-
(O-Carboxyphenyl) butyl] -6-[(1 E )
-4-Hydroxy-4-vinyl-1-octenyl] -7
-Hydroxybicyclo [3.3.0] -2-octene,
(101) to (110) 3- (4- (m-carboxyphenyl) butyl] derivatives of (91) to (100), (111) to (120), and 3 of each of (91) to (100). -[4- (p-carboxyphenyl) butyl]
Derivative,

(121) (1 S , 5 S , 6 S , 7 R )
-3- [5- (o-carboxyphenyl) pentyl]-
6-[(1 E , 3 S ) -3-hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (122) (1 S , 5 S , 6 S , 7 R ) -3
-[5- (o-carboxyphenyl) pentyl] -6-
[(1 E , 3 S ) -3-Hydroxy-4-methyl-1-
Octenyl] -7-hydroxybicyclo [3.3.0]
-2-Octene, (123) (1 S , 5 S , 6 S , 7
R ) -3- [5- (o-carboxyphenyl) pentyl] -6-[(1 E , 3 S ) -3-hydroxy-4,4
-Dimethyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (124) (1
S, 5 S, 6 S, 7 R) -3- [5- (o- carboxyphenyl) pentyl] -6 - [(1 E, 3 S) -3- hydroxy-5-methyl-1-octenyl] - 7-hydroxybicyclo [3.3.0] -2-octene, (12
5) (1 S , 5 S , 6 S , 7 R ) -3- [5-(o-
Carboxyphenyl) pentyl] -6-[(1 E , 3
S ) -3-Hydroxy-5-methyl-1-nonenyl]-
7-hydroxy-bicyclo [3.3.0] -2-octene, (126) (1 S, 5 S, 6 S, 7 R) -3-
[5- (o-carboxyphenyl) pentyl] -6-
[(1 E , 3 S ) -3-hydroxy-3-cyclopentyl-1-propenyl] -7-hydroxybicyclo [3.
3.0] -2-Octene, (127) (1 S , 5 S ,
6 S , 7 R ) -3- [5- (o-carboxyphenyl)
Pentyl] -6-[(1 E , 3 S ) -3-hydroxy-
3-Cyclohexyl] -7-hydroxybicyclo [3.
3.0] -2-Octene, (128) (1 S , 5 S ,
6 S , 7 R ) -3- [5- (o-carboxyphenyl)
Pentyl] -6-[(1 E , 4 S ) -3-hydroxy-
4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (129) (1
S, 5 S, 6 S, 7 R) -3- [5- (o- carboxyphenyl) pentyl] -6 - [(1 E, 4 R) -4- hydroxy-4-methyl-1-octenyl] - 7-Hydroxybicyclo [3.3.0] -2-octene, (13
0) (1 S , 5 S , 6 S , 7 R ) -3- [5-(o-
Carboxyphenyl) pentyl] -6-[(1 E ) -4
-Hydroxy-4-vinyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-octene, (1
31)-(140) (121)-(130) 3- [5- (m-carboxyphenyl) pentyl] derivatives, (141)-(150) (121)-(130)
3- [5- (p-carboxyphenyl) pentyl] derivative of each of the above-mentioned isocarbacyclines used in the present invention can be produced as follows. That is, the following formula (2)

[0029]

[Chemical 3]

(Where Y is a group (R³O)₂-P (=
B) A- or R^FourRepresents OC (= O) O- (here
And R³Are the same or different, and₁~ C₆hydrocarbon
A group, A and B are both oxygen atoms, or
One is an oxygen atom, the other is a sulfur yarn, and R^Four
Is C₁~ C₆A hydrocarbon group); R¹Is a hydrogen atom,
A chill group, an ethyl group or a vinyl group; R²Is straight chain
Or branched chain C₃~ C₆Alkyl group, alkenyl group
Is an alkynyl group, or C₃~ C₇Cyclo
An alkyl group; Z¹And Z²Are the same or different
Nari, Tori (C₁~ C ₇(Hydrocarbon) silyl group or it
Or an acetal bond together with an oxygen atom bound to
Is a group forming an ester bond; and n is 0 or
It is 1. ) 2,6,7-trisubstituted-3-me
Tylene bicyclo [3.3.0] octanes and the following formula
(3) X¹Zn- (CH₂)_m-W-COOR³ … (3) (where R³Is C₁~ C_TenAlkyl group, phenyl group,
Benzyl group or naphthyl group; W is phenylene
Group, C₃~ C₇Cycloalkylene group or thiophene
Is an yl group; X¹Is a halogen atom, and m is
It is an integer of 0-4. ) Organozinc compound
Is the following formula (4) CuX² … (4) (where X²Is a cyano group or a halogen atom
It ) In the presence of a cuprous salt represented by
If necessary, apply a deprotection reaction or
By further subjecting it to a salt forming reaction, the above formula (1)
It is possible to produce isocarbacyclines represented by
it can.

Starting materials for this reaction are 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by the above formula (2) and organozinc represented by the above formula (3). It is a compound.

In the above formula (2), Y is a substituent (R³
O)₂P (= B) A- or R^FourShow OC (= O) O-
Forget Substituent (R³O)₂P (= B) A-Medium, R³Is C
₁~ C₆Represents a hydrocarbon group. Both A and B are oxygen atoms
Or an oxygen atom of either A or B
And the other represents a sulfur atom. In addition, the substituent R^FourOC
(= O) O-Medium, R^FourIs C₁~ C₆Represents a hydrocarbon group
You R¹Is hydrogen atom, methyl group, ethyl group or vinyl
Represents a group. R²Is a linear or branched C₃~ C ₈A
A alkyl group, an alkenyl group or an alkynyl group,
Or C₃~ C₇Represents a cycloalkyl group. Z¹When
Z²Are the same or different, and₁~ C₇Carbonized water
And an oxygen atom to which it is attached,
A group forming an acetal bond or an ester bond
Represent. n represents 0 or 1.

(R ³ O) ₂ in the substituent represented by Y
Examples of the C ₁ -C ₆ hydrocarbon group of R ³ in P (= B) A- include a methyl group, an ethyl group, a propyl group, a phenyl group, and the like, and preferable examples of the substituent Y include diethoxy. Examples thereof include a phosphoryloxy group, a dipropoxyphosphoryloxy group, a diphenoxyphosphoryloxy group, a dimethoxythiophosphoryloxy group, a diethoxythiophosphoryloxy group, a dimethoxyphosphorylthio group and a diethoxyphosphorylthio group.

R ⁴ OC (= in the substituents represented by Y
Examples of the C _{1 to} C ₆ hydrocarbon group of R ⁴ in O) O— include a methyl group, an ethyl group, a propyl group, an allyl group, a butyl group, a hexyl group, a phenyl group, and the like. Examples include groups corresponding to each R ⁴ such as a methoxycarbonyloxy group.

Some of the 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by the above formula (2) used as starting materials for this reaction are known, and JP-A-62-61937, JP-A-62-258
No. 330 and JP-A-63-303956 describe the manufacturing method.

The isocarbacyclines used in the present invention can be administered orally or parenterally, for example, rectally, subcutaneously, intramuscularly, intravenously, transdermally, etc., for the above-mentioned purpose. Is preferably administered orally or intravenously.

For oral administration, a solid preparation or a liquid preparation can be prepared. Examples of solid preparations include tablets, pills, powders and granules. In such solid formulations, the active substance is a pharmaceutically acceptable carrier,
For example, it is mixed with sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethyl cellulose and the like. The formulation operation is carried out according to a conventional method, but it may contain an additive other than the above-mentioned carrier for formulation, for example, a lubricant such as calcium stearate or magnesium stearate.

For example, solid preparations such as those mentioned above may be mixed with an enteric substance such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer or methacrylic acid, methyl methacrylate copolymer. A solution or an aqueous solution of an organic solvent may be sprayed to form an enteric-coated preparation by applying an enteric coating. Solid preparations such as powders and granules can be wrapped in enteric-coated capsules. Liquid formulations for oral administration include, for example, emulsions, solutions, suspensions, syrups or elixirs. These formulations contain a commonly used pharmaceutically acceptable carrier such as water or liquid paraffin. An oily base such as coconut oil, fractionated coconut oil, soybean oil and corn oil can also be used as a carrier.

The pharmaceutically acceptable carrier includes, if necessary, auxiliary agents, fragrances, stabilizers or preservatives which are usually used. Liquid formulations may also be administered in capsules made of an absorbable material such as gelatin. Solid preparations for rectal administration include suppositories containing the active substance and produced by a method known per se.

The preparation for parenteral administration is administered as a sterile aqueous or non-aqueous liquid, suspension or emulsion. Non-aqueous solutions or suspensions are pharmaceutically acceptable carriers with, for example, propyl glycol, polyethylene glycol, vegetable oils such as olive oil or soybean oil, and injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents and stabilizing agents. These solutions, suspensions and emulsions can be sterilized by, for example, filtering through a bacteria-retaining filter, heating, blending a bactericide or irradiating with ultraviolet rays. Also,
It is also possible to produce a sterile solid preparation and dissolve it in sterile water or a sterile solvent for injection immediately before use. Also,
Vegetable oil such as soybean oil, phospholipids such as lecithin, and water added to a homogeneous solution of isocarbacyclines according to the present invention, for example, a pressure injection homogenizer, fat homogenized by a homogenizer such as an ultrasonic homogenizer Emulsions and the like can also be used as injections.

As the dosage form for transdermal administration, for example, ointment,
Examples include creams. These are manufactured by a usual method.

When the drug of the present invention is used as an agent for suppressing vascular hypertrophy, the amount of isocarbacyclins in the drug varies depending on the degree of symptom, age, sex, body weight, administration route, etc. of the patient. About 1 μg to 1 mg can be administered. Such a dose may be administered once to several times a day, for example, in 2 to 6 divided doses.

[0043]

The present invention will be described in more detail with reference to the following examples. In the formulas in the examples, OZ ¹ means t-butyldimethylsilyloxy group, OZ ² means trimethylsilyloxy group, and OZ ³ means t-butyldiphenylsilyloxy group.

[Reference Example 1]

[0045]

[Chemical 4]

In a 30 ml reactor zinc (0.850 g,
13 mmol) was added, and distilled tetrahydrofuran (2 ml) was added after purging with argon gas. 80 μl in it
1,2-dibromoethane was added and the mixture was heated with stirring at 65 ° C. for 1 minute, and then with stirring at room temperature for 30 minutes. Then 100 μl
Of trimethylchlorosilane was added and stirred at room temperature for 30 minutes. Then, methyl-3-iodobenzoate (2.
A solution of 62 g, 10 mmol) in dry dimethylformamide (10 ml) was added, and the mixture was stirred at 40 ° C. for 16 hours.
In a 50 ml reactor, cuprous chloride (0.990 g, 10 m
mol) and lithium chloride (0.848 g, 20 mm)
ol) in distilled tetrahydrofuran (10 ml) was prepared, and the above-mentioned reaction solution was added thereto at room temperature, and the mixture was stirred at 30 ° C. for 1 hour.
Stir for hours. (1S, 5R, 6R, 7
R) -2-Diethoxyphosphoryloxy-3-methylene-6-[(1E, 3S, 5S) -3-t-butyldimethylsilyloxy-5-methyl-1-noneyl] -7-t
-Butyldimethylsilyloxybicyclo [3.3.
0]] Octane 1a (0.672 g, 1 mmol) in dry tetrahydrofuran (10 ml) was added at room temperature,
The mixture was stirred at 30 ° C for 2 hours. The reaction solution was quenched with 200 ml of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (200 ml × 2 times), the separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. A crude product (1.97 g) was obtained. This product was subjected to silica gel column chromatography (silica gel 40 g; eluent hexane: ethyl acetate = 20: 1) to obtain the target compound 4a (0.641 g, 0.98 mmol, 9).
8%). NMR (CDCl ₃ , ppm) δ; 7.85 (2H,
m), 7.35 (2H, m), 5.45 (2H, m),
5.30 (1H, d, J = 1.2Hz), 4.10 (1
H, m), 3.90 (3H, s), 3.70 (1H,
m), 3.40 (2H, bs), 3.00 (1H,
m), 2.40 to 2.20 (3H, m), 1.95 to
1.80 (2H, m), 1.40 to 1.10 (10H,
m), 0.90 to 0.80 (18H, m), 0.09
(18H, s). IR (liquid film) cm ⁻¹ : 2955, 2920, 1725,
1607, 1590, 965, 735.

[Reference Example 2]

[0048]

[Chemical 5]

In a 50 ml reactor, zinc (0.850 g,
13 mmol) was added, and distilled tetrahydrofuran (2 ml) was added after purging with argon gas. 80 μl in it
1,2-dibromoethane was added and the mixture was heated with stirring at 65 ° C. for 1 minute, and then with stirring at room temperature for 30 minutes. Then 100 μl
Of trimethylchlorosilane was added and stirred at room temperature for 30 minutes. Then, a solution of methyl-4-bromomethylbenzoate (2.290 g, 10 mmol) in distilled tetrahydrofuran (15 ml) was added at 0 ° C, and the mixture was stirred at 0 ° C for 3 hours. Then, it cooled at -78 degreeC. A solution of cuprous chloride (0.990 g, 10 mmol) and lithium chloride (0.848 g, 20 mmol) in distilled tetrahydrofuran (10 ml) was prepared in a 100 ml reactor and cooled to -78 ° C. The above reaction liquid was added to this reaction liquid at -78 ° C, the temperature was raised to -20 ° C, the mixture was stirred for 30 minutes, and then cooled again to -78 ° C. (1S, 5R, 6R, 7R) -2 in this reaction solution
-Diphenoxyphosphoryloxy-3-methylene-6-
[(1E, 4R) -4-Methyl-4-hydroxy-1-
Octenyl] -7-t-butyldimethylsilyloxybicyclo [3.3.0]] octane 1b (0.640 g,
A solution of 1 mmol) of dry tetrahydrofuran (10 ml) was added at -78 ° C, and the mixture was stirred at -78 ° C for 2 hours. The reaction solution was quenched with 200 ml of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (200 ml × 2 times), the separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. A crude product (2.10 g) was obtained. This product was subjected to silica gel column chromatography (silica gel 40 g; eluent hexane: ethyl acetate = 2).
0: 1 to 10: 1) and the target compound 4b
(0.496 g, 0.88 mmol, 88%) was obtained.

¹ H-NMR (CDCl ₃ , ppm) δ;
7.95 (2H, d, J = 7.5Hz), 7.20 (2
H, d, J = 7.5 Hz), 5.45 (2H, m),
5.25 (1H, d, J = 1.2Hz), 3.90 (3
H, s), 3.70 (1H, m), 3.00 (1H,
m), 2.80 (2H, t, J = 7.5Hz), 2.4
0 to 1.90 (8H, m), 1.60 to 1.10 (9
H, m), 1.15 (3H, s), 1.95 to 1.80.
(9H, m), 0.09 (9H, s). IR (liquid film) cm ⁻¹ : 3340, 2956, 2930,
2915, 1682, 1611, 965, 735.

[Reference Examples 3 to 4] In the same manner as in Reference Example 1, reaction substrates 1b and 1c (1 mmol) were used, and methyl-
Reaction with a zinc compound (10 mmol) prepared from 3-iodobenzoate (10 mmol) was performed with CuCl (10
mmol) and LiCl (20 mmol). The corresponding products 4c and 4d were obtained in the yields shown in Table 1 by post-treatment and column separation after completion of the reaction. From the NMR spectra of the products shown in Table 2, it was confirmed that most of the products were target regioisomers and the reaction proceeded highly regioselectively.

[0052]

[Table 1]

[0053]

[Table 2]

4c: IR (liquid film) cm ⁻¹ : 3340, 2
956, 2932, 1715, 1607, 965, 73
5. 4d: IR (liquid film) cm ⁻¹ : 2956, 2932, 17
15,1607,965,735.

[Reference Examples 5 to 6] Zinc compounds (10 mmol) and CuCl (10 mmol) prepared from methyl-4- (bromomethyl) benzoate (10 mmol) using reaction substrates 1a and 1c in the same manner as in Reference Example 2 The reaction was carried out in the presence of LiCl (20 mmol). Corresponding product 4e by post-treatment and column separation after completion of reaction
And 4f were obtained in the yields shown in Table 3, respectively.
Table 4 shows the analysis results.

[0056]

[Table 3]

[0057]

[Table 4]

4e: IR (liquid film) cm ⁻¹ : 2955, 2
920, 1724, 1607, 1590, 965, 73
5. 4f: IR (liquid film) cm ⁻¹ : 2955, 2920, 17
24, 1607, 1590, 965, 735.

[Reference Example 7]

[0060]

[Chemical 6]

Reaction as in Reference Example 1 with reaction substrate 1d
Zinc compound (10 mm) prepared from methyl-3-iodobenzoate (10 mmol) using (1 mmol)
reaction with CuCl (10 mmol) and LiCl
(20 mmol). After the reaction was completed, 4 g of the corresponding product was obtained in a yield (86
%).

[Reference Example 8]

[0063]

[Chemical 7]

Reaction as in Reference Example 2 with reaction substrate 1c
Using (1 mmol), methyl-2- (bromomethyl)
Reaction with a zinc compound (10 mmol) prepared from benzoate (10 mmol) CuCl (10 mmol)
And LiCl (20 mmol). The post-treatment after completion of the reaction and column separation gave the corresponding product 4h in yield (86%).

[Reference Example 9]

[0066]

Embedded image

Reaction substrate 1e was reacted in the same manner as in Reference Example 2.
Using (1 mmol), methyl-2- (bromomethyl)
Reaction with a zinc compound (10 mmol) prepared from benzoate (10 mmol) CuCl (10 mmol)
And LiCl (20 mmol). The post-treatment after completion of the reaction and column separation gave the corresponding product 4i in yield (86%).

[Reference Example 10]

[0069]

[Chemical 9]

Disilyl compound 4a (950 mg, 1.45 m)
(mol) was dissolved in 10 ml of THF and stirred with ice cooling, 6 ml (2.0 equivalents) of a 1M THF solution of tetrabutylammonium fluoride was added, and the mixture was heated to 30 ° C. and stirred for 5 hours. After evaporating THF as a reaction solvent under reduced pressure, saturated ammonium chloride aqueous solution and ethyl acetate were added to the concentrate for extraction. The organic layer was washed with saturated brine, dehydrated and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained concentrate was subjected to silica gel chromatography (n-hexane: ethyl acetate = 1: 1 to 1: 2). The diol 5a was obtained by separation and purification in 586 mg (95%).

¹ H-NMR (CDCl ₃ , ppm) δ;
7.85 (2H, m), 7.35 (2H, m), 5.4
0 (2H, m), 5.30 (1H, d, J = 1.2H
z), 4.10 (1H, m), 3.90 (3H, s),
3.70 (1H, m), 3.38 (2H, bs), 3.
00 (1H, m), 2.40 to 2.20 (3H, m),
1.95 to 1.80 (2H, m), 1.40 to 1.10
(12H, m), 0.85 (6H, m). IR (liquid film) cm ⁻¹ : 3364, 2955, 2920,
2872, 1725, 1607, 1590, 1446,
1435, 1281, 1200, 1105, 1088,
995, 970, 756, 704. Mass m / e: 408 (M ⁺ -18) UV λC ₂ H ₅ OH max nm (log ε) 231.6 nm (3.94).

[Reference Examples 11-18] Reaction substrates 4b, 4c, 4d, 4e, 4f, 4 were reacted in the same manner as in Reference Example 10.
g, 4h and 4i were each used in 1 mmol and THF
The mixture was dissolved in 10 ml and stirred with ice cooling, and 4 ml (2.0 equivalents) of tetrabutylammonium fluoride in 1M THF was added to each, and the mixture was heated to 30 ° C. and stirred for 5 hours. Example 10
The resulting crude product was subjected to silica gel chromatography (n-hexane: ethyl acetate = 1: 1).
2 to 5: 1), the corresponding diols 5b, 5c, 5d, 5e, 5f, 5g, 5h and 5i were obtained at the yields shown in Table 5, respectively.

[0073]

[Table 5]

[0074]

[Table 6]

Table 7 shows compounds 5b, 5c, 5d and 5
The physical property values of e, 5f, 5g, 5h and 5i are shown.

[0076]

[Table 7]

[0077]

[Table 8]

[Reference Example 19]

[0079]

[Chemical 10]

67.5 mg of diol 5e (0.15 mm
ol) is dissolved in 6 ml of THF at room temperature, and LiOH.H
₂ O 40 mg (0.95 mmol) and H ₂ O 3
ml of an aqueous alkaline solution was added dropwise to the THF solution while stirring, and the mixture was stirred at room temperature for 26 hours, and then TLC [hexane:
It was confirmed that the raw material of ethyl acetate = 1: 4] disappeared. To the reaction mixture was added 1N-HCl (2 ml), the mixture was stirred for 30 minutes, saturated brine and ethyl acetate were added, and extraction was performed. The organic layer was washed again with saturated brine, dehydrated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained concentrate was separated and purified by silica gel column chromatography [hexane: ethyl acetate = 1: 2-1: 4 (containing 0.1% acetic acid)] to obtain 57 mg (89%) of carboxylic acid 6e. .

¹ H-NMR (CDCl ₃ , ppm) δ;
8.00 (2H, d, J = 7.5Hz), 7.25 (2
H, d, J = 7.5 Hz), 6.00 (3H, bs),
5.45 (2H, m), 5.25 (1H, d, J = 1.
2Hz), 4.15 (1H, m), 3.75 (1H,
m), 3.00 (1H, m), 2.75 (2H, t, J
= 7.5 Hz), 2.40 to 1.80 (7H, m),
1.45 to 1.20 (10H, m), 0.85 (6H,
m). IR (liquid film) cm ⁻¹ : 2955, 2924, 2872,
1692, 1613, 1424, 1318, 1289,
1179, 1090, 1015, 968, 839, 76
2,708,673. Mass m / e: 408 (M -H 2 O) UV λC 2 H 5 OH max nm (logε) 237.8 (4.38), 207.8 (4.29).

[Reference Example 20]

[0083]

[Chemical 11]

Reaction substrate 5b 1 was prepared in the same manner as in Reference Example 19.
The hydrolysis reaction was performed using 00 mg (0.24 mmol). After the reaction, post treatment and column purification gave 91 mg (96%) of the corresponding carboxylic acid 6b.

¹ H-NMR (CD ₃ OD, ppm) δ;
8.00 (2H, d, J = 7.5Hz), 7.25 (2
H, d, J = 7.25 Hz), 6.00 (3H, b
s), 5.55 (1H, m), 5.42 (1H, m),
5.25 (1H, d, J = 1.2Hz), 3.75 (1
H, m), 3.00 (1H, m), 2.80 (2H,
t, J = 10 Hz), 2.60 to 1.80 (9H,
m), 1.50 to 1.20 (7H, m), 1.15 (3
H, s), 0.90 (3H, t). IR (liquid film) cm ⁻¹ : 2956, 2930, 2915,
2842, 2664, 1682, 1611, 1576,
1455, 1424, 1320, 1291, 1179,
1090,972,847,762,706,677. Mass m / e: 394 (M -H 2 O) UV λC 2 H 5 OH max nm (logε): 237.8 (4.16), 208.0 (4.08).

[Reference Example 21]

[0087]

[Chemical 12]

Reaction substrate 5a was obtained by reacting in the same manner as in Reference Example 19.
The hydrolysis reaction was performed using 190 mg (0.446 mmol). After the reaction, post-treatment and column purification gave 184 mg (100%) of the corresponding carboxylic acid 6a.

¹ H-NMR (CD ₃ OD, ppm) δ;
7.85 (2H, m), 7.40 (2H, m), 5.6
5 to 5.30 (3H, m), 4.05 (1H, m),
3.75 (1H, m), 3.45 (2H, bs), 3.
30 (1H, m), 3.00 (1H, m), 2.40 ~
2.15 (17H, m), 0.85 (6H, m). Mass m / e: 394 (M -H 2 O) IR ( liquid film) cm ^-1: 3360,2957,2928,
2645, 1696, 1607, 1589, 1453,
1412, 1377, 1279, 1196, 1086
997,970,839,816. UV λ C ₂ H ₅ OH max nm (log ε): 229.6 (3.94), 213.0 (3.95). UV (CH ₃ OH) λmax 229.6 nm log ε3.94 λmax 213.0 nm log ε3.95.

[Reference Examples 22 to 24] Reaction was performed in the same manner as in Reference Example 19 to obtain reaction substrates 5d, 5f and 5g each at 1 mmo.
The hydrolysis reaction was carried out using 1 Corresponding carboxylic acids 6d, 6f and 6 by post-treatment and column purification after completion of the reaction
g was obtained in the yields shown in Table 7.

[0091]

[Table 9]

Table 10 shows compounds 6d, 6f and 6g.
The physical properties of

[0093]

[Table 10]

[Example 1] Measurement of inhibitory activity of DNA synthesis of human smooth muscle cells: In a 96-well plate (manufactured by Corning), 5 normal cultured cells of normal human aorta-derived vascular smooth muscle cells (manufactured by Kurabo) were prepared. ×
10 ³ cells / well were inoculated and cultured for 3 days. From the growth medium (SGM: Kurabo) to the basal medium (SG
M: manufactured by Kurabo Industries) and cultured for 24 hours. To this was added a growth medium (SGM) to which an ethanol solution (manufactured by Wako) containing the compounds obtained in Reference Examples 10, 11, 12, 14, 19 and 20 was added. After 16 hours, ³ H-thymidine (manufactured by Amersham) was added at 0.5 μCi / well, and after 8 hours, frozen at -20 ° C. After that, the mixture was returned to room temperature and melted, and then ³ H-thymidine incorporated in the nucleus was adsorbed to the glass filter using a cell harvester (manufactured by Lab Science). Then, the filter was put into a toluene scintillator solution (manufactured by Wako), and the amount of ³ H-thymidine was measured using a liquid scintillation counter (manufactured by Hulett Packard).

The results are shown in FIG. In the figure, the vertical axis represents the amount of ³ H-thymidine incorporated into the nucleus of the cell, and the horizontal axis represents the added sample and the concentration of the sample. Statistical processing was performed by student's test, and P value is shown by * mark.

From FIG. 1 the compounds 5e , 6e , 5b , 6b ,
It is found that both 5a and 5c have a growth inhibitory activity on human smooth muscle cells.

[Example 2] Measurement of cell migration inhibitory activity For the purpose of investigating the cell migration inhibitory activity of a test compound, the measurement of cell migration caused by human platelet-derived growth factor (PDGF) was carried out by measuring the normal human aorta-derived vascular smooth muscle. Using cells as migrating cells, the method of MaCarthy et al. (J. Cell. B
iol. 97 , 772-777 (1983)). That is, the inhibitory activity was measured using a Transwell chamber (Costar, registered trademark). This chamber is a membrane filter with a pore size of 8 μm (PVP-free polycarbonate filter, Nu
Cleopore (registered trademark) is divided into two layers on the upper and lower sides, and the lower surface of the filter is 5 μg of rat.
Tail collagen, type 1 (Becton Dickinson)
The surface was processed. In the chamber upper layer (100 μl),
1.5 × 10 ⁶ cells / ml (DMEM (Flow Laborat
ories) + 0.1% BSA (Nacalai Tesque)
Was added to the lower layer (600 μl), and human PDGF (manufactured by Becton Dickinson) was diluted with the same solution to a final concentration of 10 ng / ml.
At this time, the test compound was added at various concentrations in both the upper and lower layers. After standing at 37 ° C. under 5% CO ₂ for 6 hours, the filters were removed, fixed with 99.7% methanol and stained with hematoxylin and eosin. The cells adhered to the upper surface of the filter were removed with a cotton swab, and the number of cells transferred to the lower surface was measured under a high power microscope (× 200, × 4.
00) Cell nuclei were counted and determined. Usually filter 1
Five fields of view were measured per sheet. Cell migration was shown as the average number of cells in 5 fields ± standard deviation. The significance test is St
The udent's two-tailed t test was performed.

As a result, compound 5e and compound 6b
Showed a cell migration inhibitory activity of 13.9% and 20.0%, respectively, at a concentration of 10 ⁻⁷ M, as compared with the case where these drugs were not added. In addition, these compounds 5e and 6b did not show any acute toxicity.

Example 3 One tablet having the following composition was produced. Active ingredient 200 μg Lactose 180 mg Potato starch 50 mg Polyvinylpyrrolidone 10 mg Magnesium stearate 5 mg The active ingredient, lactose and potato starch are mixed and evenly moistened with a 20% ethanol solution of polyvinylpyrrolidone and passed through a 20 mm mesh sieve, 45
It was dried at 0 ° C. and passed through a 15 mm mesh again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

The active ingredient is (1S, 5S, 6S, 7
R) -3- (p-carboxybenzyl) -6-[(1
E, 4S) -4-Hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] -2-
Octene methyl ester was used.

[Example 4] A hard gelatin capsule having one capsule having the following composition was produced. Active ingredient 100 μg Microcrystalline cellulose 195 mg Amorphous silicic acid 5 mg Active ingredient, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and filled into hard gelatin capsules. As the active ingredient, the same compound as in Example 3 was typically used.

[0102]

INDUSTRIAL APPLICABILITY The vascular smooth muscle cell proliferation or migration inhibitor of the present invention is mainly used for the proliferation and migration of vascular smooth muscle cells after various angioplasty procedures, arterial bypass surgery, organ (organ) transplantation surgery and the like. It is useful as an agent for suppressing thickening and blockage of blood vessels caused by vascular hyperplasia, a preventive and therapeutic agent for preventing thickening and blockage of blood vessels (or an inhibitor for proliferation and migration of vascular smooth muscle cells), and as a preventive and therapeutic agent for arteriosclerosis.

[Brief description of drawings]

FIG. 1 Growth inhibitory activity on human vascular smooth muscle cells

Claims (14)

[Claims] 1. The following formula (1): (In the formula, W represents an ortho, meta or para phenylene group, a C ₃ -C ₇ cycloalkylene group or a thiophenediyl group, and R ¹ represents a hydrogen atom, a methyl group, an ethyl group or a vinyl group. , R ² is a linear or branched optionally substituted C ₃ -C ₉ alkyl group, alkenyl group, or alkynyl group, or C ₃
Represent -C ₇ cycloalkyl group. R ³⁰ is a hydrogen atom, C
_{1 to} C ₁₀ alkyl group, phenyl group, benzyl group, naphthyl group, or 1 equivalent of a cation, Z ¹⁰ and Z
²⁰ is the same or different and is a hydrogen atom or tri (C ₁ -C
₇ Hydrocarbon) represents a silyl group or a group that forms an acetal bond or an ester bond together with the oxygen atom to which it is bonded. n is 0 or 1, and m is an integer of 0-4. ) An inhibitor of vascular smooth muscle cell proliferation or migration, which comprises an isocarbacycline represented by the formula (4) and / or an enantiomer thereof as an active ingredient. 2. In the above formula (1), W is a phenylene group of ortho, meta or para, and Z ¹⁰ and Z
^20. The vascular smooth muscle cell proliferation or migration inhibitor according to claim 1, wherein ²⁰ is a hydrogen atom. 3. In the above formula (1), R ¹ is a hydrogen atom or a methyl group, and R ² is a linear or branched C ₃
-C ₉ alkyl group, or a C ₃ -C ₆ cycloalkyl group C ₃ -C ₉ alkyl group substituted with the alkyl linear or branched R ³ is a hydrogen atom or a C ₁ -C _10, The vascular smooth muscle cell proliferation or migration inhibitor according to claim 1 or 2, which represents a group or 1 equivalent of cation, and m is 0 or 1. 4. In the above formula (1), n = 0 and R
The vascular smooth muscle cell proliferation or migration inhibitor according to any one of claims 1 to 3, wherein ¹ is a hydrogen atom. 5. In the above formula (1), n = 1 and R
The vascular smooth muscle cell proliferation or migration inhibitor according to any one of claims 1 to 3, wherein ¹ is a methyl group. 6. The vascular smooth muscle cell proliferation or migration inhibitor according to claim 1, wherein m = 0 in the formula (1). 7. The vascular smooth muscle cell proliferation or migration inhibitor according to claim 1, wherein m = 1 in the formula (1). 8. A preventive or therapeutic agent for restenosis after PTCA, which comprises an isocarbacycline represented by the above formula (1) and / or an enantiomer thereof as an active ingredient. 9. In the above formula (1), W is an ortho, meta or para phenylene group, and Z ¹⁰ and Z
The preventive or therapeutic agent for restenosis after PTCA according to claim 8, wherein ²⁰ is a hydrogen atom. 10. In the above formula (1), R ¹ is a hydrogen atom or a methyl group, and R ² is a linear or branched C.
₃ -C ₉ alkyl or C ₃ -C ₉ alkyl group substituted with a cycloalkyl group of C _{³ ~C 6,,} R ₃ is a straight-chain or branched-chain hydrogen atom or a C ₁ -C _10, The preventive or therapeutic agent for restenosis after PTCA according to claim 8 or 9, which represents an alkyl group or 1 equivalent of a cation, and m is 0 or 1. 11. In the above formula (1), n = 0,
The preventive or therapeutic agent for restenosis after PTCA according to claim 8, wherein R ¹ is a hydrogen atom. 12. In the above formula (1), n = 1,
The preventive or therapeutic agent for restenosis after PTCA according to claim 8, wherein R ¹ is a methyl group. 13. The preventive or therapeutic agent for restenosis after PTCA according to claim 8, wherein m = 0 in the formula (1). 14. The preventive or therapeutic agent for restenosis after PTCA according to claim 8, wherein m = 1 in the above formula (1).